The main objective of this project is to determine the mode of action of thyroid hormones (T4 and T3). Studies are designed to investigate factors controlling transfer of thyroid hormones from blood to cells, their intracellular metabolism, interactions with nuclear receptors, and finally, their effect on the induction of specific messenger RNAs. The biologic materials used in these studies are: (1) rat pituitary tumors producing growth hormone (GH) and prolactin (PRL) the synthesis of which is known to be affected by thyroid hormones; and (2) cells (leukocytes and fibroblasts) from patients with inherited resistance to the action of thyroid hormone. Labeled hormones are used in the study of the kinetics and metabolism of T4 and T3. The effect of thyroid hormones and their analogues on GH and PRL synthesis are measured using specific anti-rat GH and PRL antisera. Induction of GH and PRL mRNA is quantitated by translation in cell-free systems and by hybridization techniques using purified mRNAs labeled with radioiodide. Results on thyroid hormones and analogues binding to nuclear receptors will be correlated with their effect on GH and PRL synthesis and mRNA activity and content. Abnormalities in hormone receptor interaction or expression of its activity in material obtained from patients with inherited resistance to thyroid hormone action will be used to identify important steps in the mediation of thyroid hormone action. It is also proposed to study: (1) the feedback regulation of pituitary hormone synthesis and release; (2) the characterization of PRL mRNA in human prolactin producing pituitary adenomas; (3) the factors controlling the metabolism of thyroxine-binding globulin; and (4) the interaction of T3 and TRH as related to binding to specific cell receptors. BIBLIOGRAPHIC REFERENCES: Seo, H., Refetoff, S., and Fang, V.S. Induction of Hypothyroidism and Hypoprolactinemia by Growth Hormone Producing Rat Pituitary Tumors. Endocrinol., 100:216-226, 1977. Horwitz, D.L. and Refetoff, S. Thyrotoxicosis Associated with Familial Deficiency of Thyroid-Binding Globulin. J. Clin. Endocrinol. Metab., 44:242-247, 1977.